scholarly journals Comprehensive Genomic Analysis of Metastatic Non–Clear-Cell Renal Cell Carcinoma to Identify Therapeutic Targets

2019 ◽  
pp. 1-18 ◽  
Author(s):  
Maria I. Carlo ◽  
Nabeela Khan ◽  
Ahmet Zehir ◽  
Sujata Patil ◽  
Yasser Ged ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Somatic Mutations ◽  
Clear Cell ◽  
De Novo ◽  
Genomic Analysis ◽  
Precision Oncology ◽  
Single Nucleotide Variants ◽  
Cell Renal Cell Carcinoma

PURPOSENon–clear-cell renal cell carcinoma (nccRCC) encompasses approximately 20% of renal cell carcinomas and includes subtypes that vary in clinical and molecular biology. Compared with clear cell renal cell carcinoma, nccRCC demonstrates limited sensitivity to conventional vascular endothelial growth factor– and mammalian target of rapamycin–directed agents, indicating a need for better therapies. Characterizing the genomic landscape of metastatic nccRCC variants may help define novel therapeutic strategies.PATIENTS AND METHODSWe retrospectively analyzed tumor tissue from patients with metastatic nccRCC who consented to genomic analysis of their tumor and germline DNA. A hybridization capture–based assay was used to identify single nucleotide variants and small insertions and deletions across more than 340 cancer-associated genes with germline comparison. Clinical actionability of somatic mutations was assessed using OncoKB levels of evidence. Microsatellite instability (MSI) in the tumor was investigated.RESULTSOf 116 patients included in the analysis, 57 (49%) presented with de novo metastatic disease, and 59 (51%) presented with localized disease that later metastasized. Subtype classifications included unclassified (n = 41; 35%), papillary (n = 26; 22%), chromophobe (n = 17; 15%), translocation associated (n = 13; 11%), and other (n = 19; 16%). Of all tumors, 15 (13%) had putative driver somatic alterations amenable to targeted therapies, including alterations in MET, TSC1/2, and an ALK translocation. Of 45 patients who had germline testing, 11 (24%) harbored mutations, seven of which could potentially guide therapy. Of 115 available tumors for analysis, two (1.7%) had high and six (5%) had intermediate MSI status.CONCLUSIONThe mutation profiles of metastatic nccRCC vary by subtype. Comprehensive analysis of somatic mutations, germline mutations, and MSI, interpreted via an annotated precision oncology knowledge base, identified potentially targetable alterations in 22% of patients, which merits additional investigation.

scholarly journals MP39-01 CHARACTERIZING RECURRENT AND LETHAL SMALL RENAL MASSES IN CLEAR CELL RENAL CELL CARCINOMA USING SOMATIC MUTATIONS

2017 ◽  
Vol 197 (4S) ◽  
Author(s):  
Brandon Manley ◽  
Ed Reznik ◽  
Maria Becerra ◽  
Jozefina Casuscelli ◽  
Daniel Tennenbaum ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Somatic Mutations ◽  
Clear Cell ◽  
Small Renal Masses ◽  
Cell Renal Cell Carcinoma ◽  
Renal Masses

Intratumoural heterogeneity may hinder precision medicine strategies in patients with clear cell renal cell carcinoma

2018 ◽  
Vol 71 (5) ◽  
pp. 467-471 ◽  
Author(s):  
Maria Rosaria Raspollini ◽  
Ilaria Montagnani ◽  
Rodolfo Montironi ◽  
Francesca Castiglione ◽  
Guido Martignoni ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Precision Medicine ◽  
Renal Cell ◽  
Clear Cell ◽  
Molecular Heterogeneity ◽  
Precision Oncology ◽  
Cell Renal Cell Carcinoma ◽  
Renal Sinus ◽  
The Moment

Clear cell renal cell carcinoma (ccRCC) is an heterogeneous tumour at architectural, cellular and molecular level, a reason why the 2014 International Society of Urological Pathology consensus recommended wide sampling of RCC masses to include at least 1 block/cm of tumour together with perpendicular sections of the tumour/perinephric fat interface and the tumour/renal sinus interface. Intratumoural molecular heterogeneity may be a limitation at the moment of defining precision medicine strategies based on gene mutation status. This study analyses the presence of any mutation of KRAS, NRAS, BRAF, PIK3CA, ALK, ERBB2, DDR2, MAP2K1, RET and EGFR genes in 20 tissue blocks from a case of ccRCC and its metastasis. We observed the presence of the mutation at pH1047R of PIK3CA gene in five samples of the tumour, while the remaining 15 samples did not show any mutation at PIK3CA or any other investigated gene. There is a great need to develop novel RCC sampling strategies to overcome tumour heterogeneity prior to define precision oncology strategies.

scholarly journals Identification of gene signature for treatment response to guide precision oncology in clear-cell renal cell carcinoma

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ninadh M. D’Costa ◽  
Davide Cina ◽  
Raunak Shrestha ◽  
Robert H. Bell ◽  
Yen-Yi Lin ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Treatment Response ◽  
Renal Cell ◽  
Clear Cell ◽  
Gene Signature ◽  
Precision Oncology ◽  
Cell Renal Cell Carcinoma

scholarly journals MP71-10 CLINICAL FEATURES OF RECURRENT SOMATIC MUTATIONS IN CLEAR CELL RENAL CELL CARCINOMA: A LARGE COHORT

2016 ◽  
Vol 195 (4S) ◽  
Author(s):  
Brandon J Manley ◽  
Jozefina Casuscelli ◽  
Daniel M Tennenbaum ◽  
Maria F Becerra ◽  
Almedina Redzematovic ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Clinical Features ◽  
Renal Cell ◽  
Somatic Mutations ◽  
Clear Cell ◽  
Large Cohort ◽  
Cell Renal Cell Carcinoma

scholarly journals Characterization of Hypoxia-Related Molecular Subtypes in Clear Cell Renal Cell Carcinoma to Aid Immunotherapy and Targeted Therapy via Multi-Omics Analysis

2021 ◽  
Vol 8 ◽  
Author(s):  
Weimin Zhong ◽  
Hongbin Zhong ◽  
Fengling Zhang ◽  
Chaoqun Huang ◽  
Yao Lin ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Targeted Therapy ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Somatic Mutations ◽  
Clear Cell ◽  
Molecular Subtypes ◽  
Cell Renal Cell Carcinoma ◽  
Cox Regression Analysis ◽  
Tumor Purity

Objective: Tumor hypoxia is a key factor in resistance to anti-cancer treatment. Herein, this study aimed to characterize hypoxia-related molecular subtypes and assess their correlations with immunotherapy and targeted therapy in clear cell renal cell carcinoma (ccRCC).Materials: We comprehensively analyzed copy number variation (CNV), somatic mutation, transcriptome expression profile and clinical information for ccRCC from TCGA and ICGC databases. Based on 98 prognosis-related hypoxia genes, samples were clustered using unsupervized non-negative matrix factorization (NMF) analysis. We characterized the differences between subtypes concerning prognosis, CNV, somatic mutations, pathways, immune cell infiltrations, stromal/immune scores, tumor purity, immune checkpoint inhibitors (ICI), response to immunotherapy and targeted therapy and CXC chemokines. Based on differentially expressed genes (DEGs) between subtypes, a prognostic signature was built by LASSO Cox regression analysis, followed by construction of a nomogram incorporating the signature and clinical features.Results: Two hypoxia-related molecular subtypes (C1 and C2) were constructed for ccRCC. Differential CNV, somatic mutations and pathways were found between subtypes. C2 exhibited poorer prognosis, higher immune/stromal scores, and lower tumor purity than C1. Furthermore, C2 had more sensitivity to immunotherapy and targeted therapy than C1. The levels of CXCL1/2/3/5/6/8 chemokines in C2 were distinctly higher than in C1. Consistently, DEGs between subtypes were significantly enriched in cytokine-cytokine receptor interaction and immune responses. This subtype-specific signature can independently predict patients’ prognosis. Following verification, the nomogram could be utilized for personalized prediction of the survival probability.Conclusion: Our findings characterized two hypoxia-related molecular subtypes for ccRCC, which can assist in identifying high-risk patients with poor clinical outcomes and patients who can benefit from immunotherapy or targeted therapy.

De Novo Mutations Contribute to the Development of Clear-Cell Renal-Cell Carcinoma in a 5-Year-Old Girl

2018 ◽  
Vol 16 (3) ◽  
pp. e553-e556
Author(s):  
Zhenxing Yang ◽  
Jiang Zhao ◽  
Luqiang Zhou ◽  
Yali Wang ◽  
Pin Hao ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
De Novo ◽  
De Novo Mutations ◽  
Cell Renal Cell Carcinoma

Abstract 346: Integrative genomic analysis of sporadic clear cell renal cell carcinoma

2011 ◽  
Author(s):  
Vijay R. Dondeti ◽  
Bradley Wubbenhorst ◽  
Priti Lal ◽  
John D. Gordan ◽  
Kurt D'Andrea ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Genomic Analysis ◽  
Cell Renal Cell Carcinoma

scholarly journals Genomic Analysis Reveals Novel Specific Metastatic Mutations in Chinese Clear Cell Renal Cell Carcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Hui Meng ◽  
Xuewen Jiang ◽  
Jianfeng Cui ◽  
Gang Yin ◽  
Benkang Shi ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Genomic Analysis ◽  
Renal Clear Cell Carcinoma ◽  
Genomic Feature ◽  
Cell Renal Cell Carcinoma ◽  
Hybridization Capture ◽  
Significant Difference

Clear cell renal cell carcinoma (ccRCC) accounts for more than 75% of renal cell carcinoma. Nearly 25% of ccRCC patients were diagnosed with metastasis. Though the genomic profile of ccRCC has been widely studied, the difference between localized and metastatic ccRCC was not clarified. Primary tumor samples and matched whole blood were collected from 106 sporadic patients diagnosed with renal clear cell carcinoma at Qilu Hospital of Shandong University from January 2017 to November 2019, and 17 of them were diagnosed with metastasis. A hybridization capture-based next-generation sequencing of 618 cancer-related genes was performed to investigate the somatic and germline variants, tumor mutation burden (TMB), and microsatellite instability (MSI). Five genes with significantly different prevalence were identified in the metastatic group, especially TOP1 (17.65% vs. 0%) and SNCAIP (17.65% vs. 0%). The altered frequency of PBRM1 (0% vs. 27%) and BAP1 (24% vs. 10%) differed between the metastatic and nonmetastatic groups, which may relate to the prognosis. Of these 106 patients, 42 patients (39.62%) had at least one alteration in DNA damage repair (DDR) genes, including 58.82% of metastatic ccRCC patients and 35.96% of ccRCC patients without metastasis. Ten pathogenic or likely pathogenic (P/LP) variants were identified in 11 sporadic clear cell renal cell carcinoma patients (10.38%), including rarely reported ATM (n=1), MUTYH (n=1), NBN (n=1), RAD51D (n=1), and BRCA2 (n=1). No significant difference in the ratio of P/LP variant carriers or TMB was identified between the metastatic and nonmetastatic groups. We found a unique genomic feature of Chinese metastatic ccRCC patients with a higher prevalence of alterations in DDR, TOP1, and SNCAIP. Further investigated studies and drug development are needed in the future.

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